Project Summary - Abstract Retinal prosthetic devices that use electrical stimulation have been designed in attempt to restore some vision in patients with degenerative diseases, such as retinitis pigmentosa (RP) or age-related macular degeneration (AMD). These devices function by using electrodes to stimulate local regions of retina tissue, approximating spatiotemporal patterns for representing the image facing the patient, intending to induce a pixelated percept. This has proven effective and has led to the design of multiple different prosthetic devices. In this proposal, we will take what we have learned from modeling retinal connectomes and apply them to the modeling of patho-connectomes, or connectomics volumes constructed from pathological or neurally degenerating tissues. The Tg P347L rabbit retina proceeds irreversibly through phases of retinal degeneration, altering programming and remodeling the topology and circuitry of retina. We will develop a connectome-derived submodel of each of the four degenerated states of the rabbit retina, involving the construction of pathoconnectomes of cone to ganglion cell pathways in each stage of degeneration based on TEM images of diseased retina, and the translation of each pathoconnectome to a computational model. Each of the four models will be incorporated in a multiscale hybrid Admittance Method (AM)-NEURON computational method to characterize the impact of the degeneration on neural activation induced by both natural photoreceptors and stimulating electrodes, and compare it with previously obtained results with healthy or synthetically degenerated retina. An accurate model of the degenerated retina integrated in our multiscale solver, as will be developed in the proposed work, can prove an important tool to further improve our understanding of spontaneous neural activity of the retina and support the design of effective electrodes that can incorporate the neural and anatomical information of actual degenerated retina, a task that to the best of our knowledge has never been approached to date.